Craig Venter, the man who led the private effort to sequence the human genome, still has plenty of new ideas up his sleeve

IT IS an immodest ambition from a man whom even his best friends would rarely accuse of modesty. Craig Venter's current venture is a scheme to create an artificial lifeform. He and his team at his eponymous institute, in Rockville, Maryland, have already synthesised a working virus from off-the-shelf (or, at least, out-of-the-catalogue) chemicals. But viruses do not have their own metabolisms, so not everybody counts them as truly living beings. Making a bacterium (or, at least, the genome of a bacterium) would be one of the last nails in the coffin of vitalism—the curiously persistent idea that there is something more to biology than mere physics and chemistry.

It is not just curiosity that drives the project, though. Dr Venter believes such a cell, built around the minimum genome necessary for life, would be an important tool in biotechnology. A stripped-down cell could have extra biochemical pathways engineered into it, to make useful chemical products such as drugs and fuels, without any fear that the cell's resources would be diverted to other, useless, tasks. Finding those extra biochemical pathways is also on his agenda.

Another of Dr Venter's characteristics is an ability to mix business with pleasure. To this end he has fitted out his racing yacht, Sorcerer II, as a laboratory, and is sailing round the world collecting samples. These are flown back to Rockville to undergo “whole ecosystem” genome analysis—a process that tries to extract and analyse DNA from all the bacterial species in the sample. Since bacteria are the most abundant form of life on Earth, he hopes this process will eventually reveal most of the genes on the planet.

From gadfly to guru

Dr Venter first came to public attention in 1991. At the time, he was working in the National Institutes of Health (NIH), America's huge, federal medical-research establishment. The Human Genome Project, which planned to chew its way through all 3 billion genetic “letters” that carry the instructions for making a human being, was just getting going. But all geneticists knew that only a few of those letters—probably less than 5% of them, actually constituted the genes. Dr Venter produced a short-cut that enabled people to get directly at the genes. He did not actually invent the idea of making so-called complement DNA (cDNA), by copying the messenger molecules that carry genetic information from the cell nucleus, where the genome resides, to the protein-making machinery in a cell's periphery. But he was the first person to make it work routinely.

His technique caused a kerfuffle for two reasons. First, the biologists behind the Human Genome Project feared that if the genes could be plucked so easily from the dross, then the effort to sequence all 3 billion letters would be abandoned by parsimonious politicians. Though the non-gene part of the genome is often dismissed as mere “junk DNA”, they felt (correctly) that at least some of it must be biologically important, so disentangling the whole lot was therefore necessary.

That turned out to be an idle fear. The importance of the whole genome was quickly recognised from on high, and the money kept flowing. But the second worry connected with the technique stirred up a hornet's nest whose swarm followed Dr Venter for a decade. At the behest of the NIH's lawyers, his first set of cDNAs were sent off to the patent office. DNA sequences had been patented before, so there were precedents for doing this. But the patents were for whole genes, and for genes that had solid, useful functions—namely drug production.

Dr Venter's cDNA sequences were not even whole genes. The trick that allowed him to succeed where others had failed was that he copied only a fragment of a gene—the longest fragment that a DNA-sequencing machine could analyse in one go, which is well short of the length of most full genes. These fragments enable researchers to locate genes on chromosomes. Also, enough of them taken from different parts of a messenger molecule can allow a gene to be patched back together. So they certainly had enough utility for it to be worth asking the patent office if they counted as intellectual property. But many of Dr Venter's fellow biologists were outraged by the whole idea of patenting DNA in bulk, and they made their opinions abundantly clear.

“How long will it take to make a synthetic bacterial genome? An announcement could come as soon as next year.”

In the end, the NIH withdrew its patent applications. But the affair both poisoned relations and gave Dr Venter a glimpse of a wider world. Shortly afterwards, he withdrew to set up TIGR, the Institute for Genomic Research. Thus began his quest to marry academic and commercial research in what he saw as a return to a more 19th-century way of doing things that had prevailed before the split between pure and applied science became so clear-cut.

The money for TIGR came from Wallace Steinberg, a venture capitalist. The idea was to use the cDNA technique to look for interesting genes. The commercial side of the operation would have a period of grace to examine them with a view to patenting and exploitation. The academic side could then publish interesting findings in scientific journals. It might have worked. But the commercial side, which was incorporated into a firm called Human Genome Sciences (HGS), was led by William Haseltine, a man with an ego as large as Dr Venter's, but a far more single-minded money-making agenda. The two men fell out, and the two sides of the organisation got a divorce; HGS set up its own, internal research arm.

A shotgun wedding

That, paradoxically, was the making of Dr Venter. For it freed him to try a new idea. At the time—the mid 1990s—DNA sequencing was a painstaking affair that involved breaking an organism's genome into pieces, growing the pieces in bacteria or yeast cells, extracting them again, breaking them up still further, feeding the small bits into a sequencing machine, and then trying to put the whole jigsaw puzzle back together in reverse. Dr Venter suspected it could be done much faster by shredding entire genomes in a single step, sequencing the bits, and using a computer to fit those bits back together. Again, the idea had been kicking around for a while. But with the aid of a biologist called Hamilton Smith, he made it work.

The technique in question was called whole-genome shotgunning. It revolutionised the field. Its first fruits were the genomes of bacteria. Indeed, one of Dr Venter's favourite anecdotes is how he received a letter from a funding committee denying his application for money to deploy the technique at precisely the moment he was putting the finishing touches to a paper describing the first bacterial genome ever sequenced. But it occurred to Dr Venter that larger genomes than those of germs might fall to the new technology. And, by a lucky co-incidence, the bosses of PerkinElmer, the firm that made the DNA-sequencing machines used by Dr Venter and most other workers in the field, were having similar ideas.

The resulting collaboration was called Celera Genomics, and its goal was to produce a privately financed version of the human genome's sequence. If genomic officialdom had had qualms about the patenting of cDNA, it had paroxysms at the idea that the entire human genome might somehow fall into private hands. The result was a massive reorganisation and speeding up of the public Human Genome Project, with a view to putting huge quantities of the sequence into the public domain, and so beyond the reach of Celera's patent lawyers.

In fact, Dr Venter had never intended to patent more than a few hundred crucial (and, he hoped, ultimately profitable) genes. Indeed, some accounts from inside Celera at the time suggest he was almost as much at loggerheads with the firm's lawyers as were the public project's biologists. As in the case of TIGR, the biologist and the businessman were uncomfortable in the same skin. Instead, what he had in mind was a business that would deliver “value-added” biological information to drug companies and other researchers, much as Bloomberg packages and delivers financial data.

The outcome of the race between Celera and the public project was a politically brokered tie in which Dr Venter and his rivals shared a platform with President Bill Clinton. It was good publicity. But in the end, Celera failed. It delivered the genome (one of the six individuals sequenced being Dr Venter himself), but failed to deliver profits. The added value which it promised was not deemed valuable enough by potential customers and Dr Venter, in the time-honoured phrase of public-relations offices everywhere, “left to pursue other interests”—the main ones being synthetic biology and whole-ecosystem sequencing.

How long it will take to make a synthetic bacterial genome remains to be seen, though an announcement could come sometime next year. But whole-ecosystem analysis is already yielding staggering results. The technique is a logical extension of whole-genome analysis. The DNA in a water sample is extracted, shredded and sequenced, and the sequences assembled by computer. If the technique works properly, it will sort out the individual bacterial genomes without there ever being a need to culture the species to which those genomes belong.

Towards the planetary genome

The need to culture has held bacteriology back since its earliest days. Culturing bacteria is time-consuming, and many bacteria do not thrive in captivity. Bacteriologists knew that, of course, but they could only guess how little they knew. And the answer seems to be that they knew almost nothing. Before the first collecting jar was dipped in the water in Sorcerer's wake (off the coast of Bermuda, as it happened), about 5,000 species of bacteria had been classified. That single sampling site, Dr Venter reckons, yielded 47,000 new species, and the other sites (one every 200 nautical miles, or 370km, between Bermuda and Sydney, via the Pacific) have been just as productive. Altogether, Dr Venter thinks he has identified some 5m new genes. Not yet a genome for the planet. But a start.